The long-term goal of this research is to elucidate the apparently intertwined molecular bases of plant immunity to human pathogens and plant susceptibility to plant pathogens. We use the model Arabidopsis-Pseudomonas syringae/enterohemorrhagic Escherichia coli (EHEC) pathosystem for this research. A recent study shows that transgenic expression of P. syringae virulence protein AvrPto (a putative GTPase activating protein) suppresses the cell wall-based extracellular immunity in Arabidopsis, allowing substantial multiplication of not only P. syringae, but also EHEC O157:H7. The central hypotheses to be tested in this research are: i) Plants uses the cell wall-based immunity to ward off many microbes, including human pathogens, and ii) P. syringae virulence proteins suppress this host immunity by either inhibiting polarized extracellular vesicle trafficking (e.g., AvrPto) or down-regulating the microbe-activated immunity signal transduction pathway (e.g., HopPtoD2, a protein tyrosine phosphatase). Specific aims are: 1) Investigation of the activation of Arabidopsis cell wall-based extracellular immunity by human pathogens, 2) Genome wide identification of P. syringae virulence proteins that suppress host cell wall-based immunity, 3) Elucidation of the mechanism by which AvrPto inhibits polarized extracellular vesicle trafficking, 4) Elucidation of the mechanism by which HopPtoD2 down-regulates the immunity-associated signal transduction pathway, and 5) Characterization of Arabidopsis cell wall-based immunity using functional genomic methods. A combination of molecular genetic, cell biological, transgenic, microscopic, and pathogenesis methods will be used. The proposed research will not only contribute to the fundamental knowledge of how bacterial pathogens cause disease in higher eukaryotes, but also will provide insight into the poorly understood molecular basis of contamination and colonization of plants by human pathogens, which have become a major public health and bioterror concern due to food poisoning from consuming fresh vegetable foods.